It has been shown by many epidemiological surveys that, alongside of hypertension and smoking, hypercholesterolemia is one of the three major risk factors for atherosclerotic diseases such as myocardial infarction, angina pectoris, and cerebral infarction. Therefore, adequate control of blood cholesterol concentration is of paramount importance for the prevention and treatment of atherosclerotic diseases such as ischemic heart diseases. As drugs for lowering cholesterol in blood, drugs which inhibit bile acid absorption by binding with bile acid, such as colestyramin and colestipol (disclosed in e.g. U.S. Pat. No. 4,027,009), drugs which inhibit acyl-CoA cholesterol O-acyltransferase (ACAT) to suppress the intestinal absorption of cholesterol, such as melinamide (disclosed in French Patent 1476569), and drugs which inhibit cholesterol biosynthesis, such as lovastatin (U.S. Pat. No. 4,231,938), simvastatin (U.S. Pat. No. 4,231,938), (U.S. Pat. No. 4,444,784), and pravastatin (U.S. Pat. No. 4,346,227), all of which are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), are attracting many attentions. However, inhibition of HMG-CoA reductase results in inhibition of not only cholesterol biosynthesis but also biosynthesis of other vital physiological substances such as ubiquinones, dolichols, and heme A. Accordingly, these drugs are not fully satisfactory for use as medicines in view of the consequent adverse effects.
Meanwhile, liver low-density lipoprotein (LDL) receptors are playing a principal role in cholesterol homeostasis. Cholesterol circulating in the form of LDL is eliminated from plasma by specific LDL receptors, and taken up in the cells by the mechanism of receptor-mediated intracellular uptake. Taken up in the cells, LDL particles are decomposed by the lysosomes, whereupon cholesterol is released to increase the intracellular concentration of free cholesterol. The increased free cholesterol concentration transmits a signal to liver cells to lower the transcription rate of the gene of the key enzyme in the cholesterol biosynthetic pathway, and decrease biosynthesis of cholesterol. Furthermore, the LDL receptor mRNA and protein are down-regulated by increased intracellular cholesterol so that the capacity of liver to eliminate the excess LDL cholesterol from plasma is compromised. Therefore, the mechanism for independent up-regulation of LDL receptors is expected to lower the plasma cholesterol level still more remarkably and it is possible that any drug as up-regulating LDL receptors could be a novel hypolipemic agent.
Incidentally, there is not a single known compound structurally analogous to the compound of the present invention.
In the above state of the art, development of a new type of antihyperlipemic drug having low-density lipoprotein (LDL) receptor up-regulating activity has been awaited.